WINART FORTE

Indications

• Uncomplicated malaria caused by Plasmodium falciparum
• Malaria treatment in combination with lumefantrine

Dosage

Children: Refer to the BNF for Children for appropriate dosing information.

Adults: Refer to specific guidelines; typically, artemether is administered in a combination therapy regimen with lumefantrine.

Mechanism of action

Artemether interacts with ferriprotoporphyrin IX (heme) in the acidic vacuole of malaria parasites, leading to the generation of cytotoxic radical species. This interaction involves the activation of the drug by reduced heme or ferrous iron, resulting in the formation of oxygen-centered radicals that subsequently convert into carbon-centered radicals. These radicals are toxic to the parasites, thereby inhibiting their growth and reproduction.

Pharmacodynamics

Artemether is rapidly metabolized to its active metabolite, dihydroartemisinin. It primarily targets the erythrocytic stages of Plasmodium falciparum by inhibiting nucleic acid and protein synthesis. The drug has a rapid onset of action, providing quick symptomatic relief by significantly reducing the number of circulating malarial parasites. In combination therapy with lumefantrine, artemether enhances overall treatment effectiveness and contributes to a higher clinical cure rate.

Pharmacokinetics

Artemether is absorbed quickly, with a rapid onset of action. It is metabolized in the liver to dihydroartemisinin, which is the active form responsible for its antimalarial effects. The drug is eliminated from the body relatively quickly, while lumefantrine, which has a longer half-life, aids in clearing any residual parasites. This pharmacokinetic profile supports the use of artemether in combination therapies for malaria.

Adverse effects

• nausea
• vomiting
• dizziness
• headache
• fatigue
• abdominal pain
• anemia
• QT prolongation

Interactions

• mitotane+artemether with lumefantrine: Severe (decreases exposure)
• mitotane+artemether: Severe (decreases exposure)
• rifampicin+artemether: Severe (decreases exposure)
• grapefruit juice+artemether: Unknown (increases exposure)
• efavirenz+artemether: Unknown (decreases concentration)
• etravirine+artemether: Unknown (decreases exposure)

Precautions

• Monitor for signs of hypersensitivity reactions
• Use with caution in patients with pre-existing QT prolongation
• Assess liver function before use, as hepatic impairment may alter drug metabolism

Pregnancy

Artemether is categorized as pregnancy category C. It should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Artemether is excreted in breast milk. Caution should be exercised when administering to nursing mothers.

Storage

Store at room temperature, away from moisture and heat. Protect from light.

Formulations

• artemether/lumefantrine combination tablets
• artemether oral solution

Dosage

Children: Refer to specific product formulations for details, as dosages of excipients vary based on the formulation and are not standardized.

Adults: Refer to specific product formulations for details, as dosages of excipients vary based on the formulation and are not standardized.

Mechanism of action

As excipients, magnesium compounds do not have a specific mechanism of action related to therapeutic effects. However, they contribute to the physical and chemical stability of the drug formulation, ensuring proper release and absorption characteristics. For example, magnesium stearate is a common lubricant used in tablet formulations; it prevents ingredients from sticking to manufacturing equipment during production.

Pharmacodynamics

Mgexcipients do not exert pharmacodynamic effects as they are considered inert substances in drug formulations. They do not interact with biological targets in a manner that produces therapeutic outcomes. Their primary role is to enhance the formulation's physical properties, such as flow, compressibility, and stability.

Pharmacokinetics

Since magnesium excipients are primarily inert, they do not generally undergo absorption, distribution, metabolism, or excretion in the same manner as active pharmaceutical ingredients. Their presence in formulations is meant to facilitate the manufacturing and delivery of the active drug rather than to exert therapeutic effects.

Indications

• Uncomplicated malaria caused by Plasmodium falciparum
• Malaria prophylaxis in patients at high risk

Dosage

Children: Refer to the BNF for Children for specific dosing guidelines.

Adults: Refer to the BNF for specific dosing guidelines.

Mechanism of action

Mglumefantrine exhibits its antimalarial effects through the inhibition of heme polymerization. It accumulates in the food vacuole of the malaria parasite, where it interacts with heme, preventing the polymerization to hemozoin. This leads to toxic effects on the parasite, ultimately resulting in its death.

Pharmacodynamics

The drug shows a dose-dependent relationship with its pharmacological effects. Mglumefantrine has a long half-life, allowing for sustained drug levels in the bloodstream, which aids in reducing parasitemia and improving patient recovery from malaria. Its activity is particularly potent against the asexual blood stages of the malaria parasite.

Pharmacokinetics

Mglumefantrine is well-absorbed following oral administration, with peak plasma concentrations reached within a few hours. It undergoes extensive hepatic metabolism, predominantly via cytochrome P450 enzymes, and is eliminated primarily through the feces. The drug has a long elimination half-life, which supports less frequent dosing regimens.

Contra-indications

• Hypersensitivity to mglumefantrine or any component of the formulation
• Severe liver impairment

Adverse effects

• Nausea
• Vomiting
• Diarrhea
• Headache
• Dizziness
• Fatigue
• Palpitations
• Prolonged QT interval

Interactions

• Concomitant use with drugs that prolong the QT interval may increase the risk of arrhythmias
• Potential interaction with antimalarial drugs that affect hepatic metabolism

Precautions

• Monitor for signs of hypersensitivity reactions
• Use with caution in patients with pre-existing cardiovascular conditions
• Monitor liver function in patients receiving long-term treatment

Pregnancy

Limited data available, use only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

Unknown if excreted in human milk, use with caution.

Storage

Store in a cool, dry place, away from light and moisture.

Formulations

• Tablets
• Oral suspension

Mechanism of action

Involves an interaction with ferriprotoporphyrin IX (“heme”), or ferrous ions, in the acidic parasite food vacuole, which results in the generation of cytotoxic radical species. The generally accepted mechanism of action of peroxide antimalarials involves interaction of the peroxide-containing drug with heme, a hemoglobin degradation byproduct, derived from proteolysis of hemoglobin. This interaction is believed to result in the formation of a range of potentially toxic oxygen and carbon-centered radicals. Artemether (AM) is an antimalarial drug derived from artemisinin (Qinghaosu), an extract of the herb Artemisia annua L., sweet wormwood. Its antiparasitic effect is that of a schizontocide and is explained by rapid uptake by parasitized erythrocytes and interaction with a component of hemoglobin degradation resulting in formation of free radicals. It has been shown to exhibit a high clinical cure rate. Two theories have been put forward for the mode of antimalarial action of the artemisinin antimalarials, in accodance with the known properties of peroxides with medicinal activity. The first assumes that the artemisinins must be activated by contact with either reduced haem (ferrous haem, Fe(ll)PPIX) or non-haem ferrous iron (exogenous iron), causing cleavage of the peroxide to generate oxygen-centered radicals (alkoxy radicals') which are then presumed to be converted into carbon-centered radicals by transfer of proximate hydrogen atoms from the periphery of the peroxide molecule. These carbon-centered radicals are then thought to alkylate sensitive, yet unspecified, biomolecules in the parasite. A second theory argues for a process in which the intact artemisinin binds to a site within a vital protein in the parasite. The act of binding causes the peroxide to be converted to hydroperoxide or similar open peroxide, which in accordance with known properties of such compounds, generates one or more active chemical entities, either oxidizing agents or oxygen transfer agents per se, or oxygen-centered free radicals. This would be associated with the binding process. In such a way, the artemisinins might act as (irreversibile) inhibitors. Iron may, or may not, be associated with the activation process. No specific biological target in the parasite has yet been identified in support of this theory, but it may be membrane-bound proteins. A 2025 systematic review notes Artemether's pharmacological activity is antimalarial.

Pharmacodynamics

In the body, artemether is metabolized into the active metabolite metabolite dihydroartemisinin. The drug works against the erythrocytic stages of <i>P. falciparum</i> by inhibiting nucleic acid and protein synthesis. Artemether is administered in combination with lumefantrine for improved efficacy. Artemether has a rapid onset of action and is rapidly cleared from the body. It is thought that artemether provides rapid symptomatic relief by reducing the number of malarial parasites. Lumefantrine has a much longer half life and is believed to clear residual parasites.